PROJECT SUMMARY/ABSTRACT Dr. Teresa M. Lee, MD, MS is a Pediatric Cardiologist, Clinical Geneticist, and Assistant Professor of Pediatrics on the investigator track with 75% protected research time at Columbia University Medical Center. With her training and expertise, she has the highly sought-after set of skills needed to bridge the fields of genetics and cardiology to fill an important niche in translational molecular genetic cardiology research. Her current investigative efforts are directed towards identifying the genetic causes of infantile cardiomyopathy ? a research goal in line with the mission of the NHLBI to stimulate discoveries about the causes of disease that can enable the translation of basic discoveries into clinical practice. Cardiomyopathy is a disease of the heart muscle which often results in heart failure, cardiac transplantation, or death. Infants have the worst prognosis, the highest genetic causality, and the least known about the underlying cause of their disease. In particular, congenital forms of cardiomyopathy progress rapidly and are often fatal. Many of these disorders are related to alterations in the RAS-mitogen-activated protein kinase pathway. In preliminary studies, Dr. Lee has identified a novel MRAS variant believed to cause the protein to be constitutively active ? leading to the development of cardiac hypertrophy via the RAS signaling pathway. She hypothesizes that infants with cardiomyopathy frequently have highly pathogenic de novo variants as the cause of their cardiomyopathy, and that the RAS signaling pathway is commonly involved in disease pathogenesis. The specific goals of this K23 proposal are to test this central hypothesis through novel gene discovery studies and the development of cellular and mouse models to study the effects of MRAS. Results from this study will impact knowledge about the genetic etiology of infantile cardiomyopathy, their underlying pathophysiology, and common pathways which can serve as future targets for pharmacologic and therapeutic intervention in the broader field of cardiomyopathy. Moreover, it serves to provide Dr. Lee with the necessary training to become an independent physician-scientist with a career focused on collaborative, patient-oriented research centered on understanding the genetic causes of cardiomyopathy in infants and children. Superb mentorship, access to abundant resources, unrivaled access to the largest and most diverse patient population, and the rich intellectual environment across Departments and Schools at Columbia University will help this candidate be well-positioned to establish an independent, life-long career focused on pediatric cardiomyopathy research that will address the inadequacies of our current treatment strategies and outcomes.